Processes for the preparation of pesticides and intermediates

ABSTRACT

There is disclosed a process for the preparation of an indanylamine compound of general formula ##STR1## wherein R 1  represents an optionally substituted alkyl group, and R 2 , R 3  and R 4  independently represent a hydrogen atom or an optionally substituted alkyl group, the process including the steps of hydrogenating a compound of general formula ##STR2## wherein R 1 , R 2 , R 3  and R 4  are as described above and R 5  and R 6  independently represent a halogen atom, a hydroxyl, nitro or cyano group, or an optionally substituted alkyl, alkoxy, alkoxycarbonyl, alkylcarboxy or alkylamino group provided that R 5  and R 6  represent different atoms or groups, and subsequent rearrangement and derivatization of the product thereof. Compounds of general formula I may be used to prepare preferred stereoisomers of fungicidal N-indanyl carboxamide compounds.

This invention relates to a process for the preparation of pesticidesand intermediates. Particularly, although not exclusively, the inventionrelates to the predominant preparation of preferred stereoisomers ofindanylamine compounds which may be used to predominantly preparepreferred stereoisomers of fungicidal N-indanyl carboxamide derivatives.

European Patent Application Number 0 280 275 (Mitsubishi KaseiCorporation) describes fungicidal N-indanyl carboxamide derivatives ofgeneral formula: ##STR3## wherein R represents a lower alkyl group, n isan integer from 1 to 6 and A represents various optionally substitutedheterocyclic groups.

Japanese Laid-Open Publication No. 92-54173 (Mitsubishi KaseiCorporation) discloses an optionally active N-indanylthiazolecarboxamide having enhanced fungicidal activity and a process for thepreparation thereof. The particular compound disclosed is4-methyl-N-(3R-1,1,3-trimethylindan-4-yl)thiazole-5-carboxamide. Theprocess for the preparation of the compound involves optically resolving4-methyl-N-(1,1,3-trimethylindan-4-yl)thiazole-5-carboxamide using, forexample, an optical isomer separating column. As a consequence of theprocess described, the yield of the preferred enantiomer may berelatively low.

This invention is based on the discovery of a novel process for thepreparation of indanylamine compounds which may be used in thepreparation of preferred stereoisomers of fungicidal N-indanylcarboxamide derivatives.

According to a first aspect of the present invention, there is provideda process for the preparation of an indanylamine compound of generalformula ##STR4## wherein R¹ represents an optionally substituted alkylgroup, and R², R³ and R⁴ independently represent a hydrogen atom or anoptionally substituted alkyl group, the process including the steps ofhydrogenating a compound of general formula ##STR5## wherein R¹, R², R³and R⁴ are as described above and R⁵ and R⁶ independently represent ahalogen atom, a hydroxyl, nitro or cyano group, or an optionallysubstituted alkyl, alkoxy, alkoxycarbonyl, alkylcarboxy or alkylaminogroup provided that R⁵ and R⁶ represent different atoms or groups, andsubsequent rearrangement and derivatisation of the product thereof.

The process has been found to be advantageous in producing compounds ofthe general formula I in which a preferred stereoisomer of the compoundmay predominate. It is believed that this arises from the chiral natureof the group R⁵ R⁶ CH-- in the compound of general formula II. Oneconfiguration of the group R⁵ R⁶ CH-- suitably predominates in thecompound of general formula II. Preferably, the compound of generalformula II consists essentially of a single configuration of the groupR⁵ R⁶ CH--.

Generally, when any moiety described herein comprises an alkyl group,this alkyl group may be linear or branched and may suitably contain 1 to4 carbon atoms, suitable examples being methyl, ethyl and propyl. Whenany groups are designated as being optionally substituted, thesubstituent groups which are optionally present may be any of thosecustomarily employed in the development of pesticidal compounds, and/orthe modification of such compounds to influence theirstructure/activity, persistence, penetration or other property. Inrelation to moieties defined herein which comprise an optionallysubstituted alkyl or alkylene group, specific examples of suchsubstituents include halogen, especially fluorine, chlorine or bromineatoms, and nitro, cyano, hydroxyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, (C₁₋₄alkoxy)carbonyl groups, amino and C₁₋₄ alkylamino groups. It ispreferred, however, that alkyl moieties are unsubstituted orhalogen-substituted and that alkylene moieties are unsubstituted or onlysubstituted by alkyl.

In the context of this specification, the term "predominant" (or liketerm) indicates greater than 50% and, more preferably, greater than 60%.

Preferably, R¹ represents an unsubstituted alkyl group. R¹ preferablyrepresents a C₁₋₂ alkyl group. More preferably, R¹ represents a methylgroup.

Preferably, R² represents a hydrogen atom or a C₁₋₂ alkyl group. Morepreferably, R² represents a hydrogen atom.

Preferably, R³ and R⁴ independently represent a hydrogen atom or a C₁₋₂alkyl group. More preferably, R³ and R⁴ represent a C₁₋₂ alkyl group.Especially preferred is the case wherein R³ and R⁴ represent a methylgroup.

Preferably, R⁵ represents an optionally substituted C₁₋₆ alkyl group.More preferably, R⁵ represents a C₁₋₄ alkyl group. Especially preferredis the case wherein R⁵ represents a methyl group.

Preferably R⁶ represents a halogen atom, a hydroxyl group or anoptionally substituted alkoxy, alkoxycarbonyl or alkylcarboxy group.More preferably, R⁶ represents a halogen, especially a chlorine, atom,or a hydroxyl or C₁₋₆ alkylcarboxy group. Especially preferred is thecase wherein R⁶ represents a chlorine atom or a hydroxyl or acetoxygroup.

In said hydrogenation step, said compound of general formula II ishydrogenated to form a compound of general formula ##STR6## wherein R¹,R², R³, R⁴, R⁵ and R⁶ are as described above.

The reactants and conditions for said hydrogenation step are preferablysuch as to lead to the predominant formation of a preferreddiastereomeric form of said compound of general formula III.

The hydrogenation reaction of said compound of general formula II ispreferably carried out in the presence of a heterogenous catalyst. Saidheterogenous catalyst preferably includes a transition metal catalyst, apalladium/carbon catalyst being especially preferred.

The hydrogenation reaction is preferably carried out using gaseoushydrogen.

The hydrogenation reaction is preferably carried out in the presence ofan organic solvent. Said solvent is preferably polar. Preferred solventsare alcohols or lower alkanoic acids, with methanol and acetic acidbeing especially preferred.

The hydrogenation reaction is preferably carried out at ambienttemperature and pressure. Suitably, a solution comprising said compoundof general formula II and said heterogenous catalyst in said organicsolvent is stirred in a hydrogen atmosphere over an extended period oftime. After the hydrogenation reaction, the catalyst is removed,suitably by filtration, and the compound of general formula III isolatedby standard procedures.

Said compound of general formula III is then preferably treated toeffect rearrangement and derivatisation, for example, hydrolysis,thereof, in order to prepare the compound of general formula I. Thetreatment preferably includes slow addition of the compound of generalformula III to a strong acid. This initial step may lead to theformation of an intermediate compound of general formula ##STR7## whichneed not be isolated.

The compound of general formula IV may be hydrolysed by the addition tothe reaction mixture of water and a weak acid, for example an alkanoicacid such as acetic acid. The reaction mixture is suitably then heated.The desired compound of general formula I may then be isolated from thereaction mixture by standard procedures.

It will be appreciated that the compound of general formula IIIdescribed above has at least two chiral atoms, namely the C-4 atom whichcarries the group R¹ and the carbon atom of the group R⁵ R⁶ CH-- and,therefore, the compound may exist in various diastereomeric forms. Ithas been found that stereoisomeric configurations are generallymaintained in the process on going from compounds of general formula IIIto compounds of general formula I. For example, in a preferredembodiment in which R¹, R³ and R⁴ represent methyl groups, R² representsa hydrogen atom and R⁵ and R⁶ are as described in any statement herein,it has been found that the diasteriomeric purity of the compound ofgeneral formula III prepared in the process leads to compounds ofgeneral formula I with similar enantiomeric purity.

Also, by using in the process of the first aspect, a compound of generalformula II having a group R⁵ R⁶ CH-- of appropriate chirality and bystereoselective hydrogenation of the compound of general formula II, thestereochemistry of the compound of general formula III, and subsequentlythe compound of general formula I, may be controlled so as to lead tothe predominant formation of a preferred stereoisomer. For example, inthe preferred embodiment described above in which R¹, R³ and R⁴represent methyl groups and R² represents a hydrogen atom, the reactionmay be controlled so as to lead to the predominant formation of apreferred enantiomer of the compound of general formula I.

The compound of general formula II may be prepared by reacting acompound of general formula. ##STR8## wherein a preferred enantiomerpredominates, R⁵ and R⁶ are as described above and L¹ is a leavinggroup, with a compound of general formula ##STR9## wherein R¹, R², R³and R⁴ are as described above.

L¹ may represent a halogen atom, especially a chlorine atom, or ahydroxyl, azide, alkoxy, optionally substituted phenoxy, or alkylcarboxygroup. Preferably, said compound of general formula V is an anhydridewherein L¹ represents a group of general formula ##STR10## wherein R⁵and R⁶ are as described above; or a group of general formula: ##STR11##wherein R⁷, R⁸ and R⁹ independently represent a hydrogen atom or anoptionally substituted alkyl, alkenyl, alkynyl or phenyl group.Preferably, R⁷, R⁸ and R⁹ represent methyl groups.

In preferred embodiments, said compound of general formula V representsanhydrides of L-(+)-acetoxylactic acid or S-(-)-2-chloropropionic acid.Compounds of general formula V are commercially available and/or may beprepared using standard procedures.

The compound of general formula VI may be prepared using standardprocedures.

Said compounds of general formula II, III and IV are believed to benovel and the compounds per se and the processes for the preparation ofthe compounds constitute further aspects of the present invention.

The compound of general formula I may be reacted with a compound ofgeneral formula ##STR12## wherein L² represents a leaving group and Arepresents a group of general formula ##STR13## wherein X represents ahalogen atom, a methyl group or a trifluoromethyl group, Y represents ahydrogen atom, a halogen atom, a lower alkyl group, an amino group, amercapto group or a lower alkylthio group, R¹¹ represents a methyl groupor a trifluoromethyl group, and R¹² and R¹³ independently represent ahydrogen atom or a methyl group to prepare a pesticidal, moreparticularly a fungicidal, compound of general formula ##STR14##

Preferably, L² represents a halogen atom, especially a chlorine atom, ora hydroxyl, azide, alkoxy, optionally substituted phenoxy, alkylcarboxyor alkoxycarboxy group. More preferably, L¹ represents an alkoxy group.

Preferably, A represents a group of general formula ##STR15## wherein Xand Y are as described above.

More preferably, A represents a group of formula ##STR16##

The reaction of said compounds of general formula I and VII may becarried out in a process analogous to the process described in JapaneseLaid-Open Publication No. 92-54173. In the preparation of the compoundof general formula VIII, the reactants are preferably mixed together ina solvent. A preferred solvent includes an alcohol and an alkali metalalkoxide, The reaction is preferably carried out at an elevatedtemperature, suitably at the reflux temperature. The desired product maybe isolated using standard procedures.

The invention extends to a compound of general formula I when preparedby the process of the first aspect per se.

According to a second aspect of the present invention, there is provideda process for the preparation of a compound of general formula VIII asdescribed above, the process comprising reacting a compound of generalformula I as described above with a compound of general formula VIIdescribed above.

The invention extends to a compound of general formula VIII whenprepared by the process of the second aspect per se.

In a preferred embodiment, in the compound of general formula I preparedin the process of the first aspect, R¹ represents a methyl group, R²represents a hydrogen atom and R³ and R⁴ both represent a methyl group.The C-3 atom to which the group R¹ is attached is preferablypredominantly "R" (rectus) configuration.

The invention will now be described further with reference to thefollowing Examples.

EXAMPLE 1 Preparation of 4-Amino-1,1,3-Trimethylindane[Enriched in3R-4-Amino-1,1,-3-Trimethylindane Stereoisomer]

[R¹ =methyl; R² =H; R³ =R⁴ =methyl in the compound of general formula I]

A. ROUTE NO. 1 (i) Preparation of1-(2S-2-Chloropropionyl)-1,2-Dihydro-2,2,4-Trimethylquinoline

[R¹ =methyl; R² =hydrogen; R³ =R⁴ =methyl; R⁵ =methyl; and R⁶ =chlorinein the compound of general formula II].

To S-(-)-2-chloropropionic acid (10.3 g, 95 mmol.) in tetrahydrofuran(70 ml) was added N,N'-dicyclohexylcarbodiimide (9.83 g, 47.5 mmol) andthe mixture stirred at ambient temperature for 1.5 hours. TheN,N'-dicyclohexylurea by-product was filtered off and the filtrateconcentrated to give the crude anhydride (10.8 g) which was used withoutfurther purification. This was mixed with1,2-dihydro-2,2,4-trimethylquinoline (6.5 g, 37.5 mmol) and heated at100°-105° C. for 8 hours under a nitrogen atmosphere. After cooling, theproducts were dissolved in diethyl ether and back-washed (2×5N HCl, thensodium bicarbonate), dried and freed of solvent to give the amide (9.9g, purity by gas chromatography 89%, yield 89% ).

NMR (CDCl₃): δ (ppm) 1.48,1.55,2.05,2.06(3H,s), 1.67(3H,d,J=7Hz),4.74(1H,q,J=7Hz), 5.52(1H,s), 6.83(1H,bd), 7.1-7.3(3H,m).

Addition of chiral solvating agent[(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol] showed the material tocomprise a 3/1 enantiomer mixture of the 2S/2R isomers respectively.

Mass Spectometry: M+' 263/265 (3/1).

(ii) Preparation of1-(2-Chloropropionyl)-1,2,3,4-Tetrahydro-2,2,4-Trimethylquinoline

[R¹ =methyl; R² =H; R³ =R⁴ =methyl; R⁵ =methyl; and R⁶ =chlorine in thecompound of general formula III].

A solution of the compound prepared in A(i) (2 g) in methanol (25 ml)containing 5% Pd/C catalyst (0.2 g) was stirred in a hydrogen atmosphereat ambient temperature and pressure for 15 hours. The catalyst wasfiltered and the solvent removed to give the tetrahydroquinoline (1.7g); crude yield 84%.

This product comprised a 15/5/3/1 mixture of the (4R,2S), (4S,2R),(4S,2S) and (4R,2R) isomers respectively as determined by gaschromatography analysis of diastereomer ratio and the enantiomericpurity of the starting material.

NMR (CDCl₃); [4R,2S or 4S,2R isomer] δ (ppm): 1.34,1.54(3H,d,J=Hz),1.52,1.63(3H,s), 2.72(1H,m), 4.58(1H,q,J=Hz), 6.70(1H,bd),7.1-7.3(3H,m).

[4S,2S or 4R,2R isomer] δ (ppm): 1.33,1.69(3H,d,J=7Hz), 1.48,1.67(3H,s), 2.82(1H,m), 4.75(1H,q,J=7Hz), 7.1-7.3(3H,m).

(iii) Preparation of 4-Amino-1,1,3-Trimethylindane

To 98% sulphuric acid (2 ml) was added the compound prepared in A(ii)(1.7 g) and heated at 50°-60° C. for 30 minutes. After cautious additionof water (2 ml) and acetic acid (0.5 ml), the mixture was refluxed for 3hours. The aminoindane product was isolated by basification (aq.NH₃) andextraction into diethyl ether. Yield 1.1 g. (83% over two steps).

NMR (CDCl₃): δ (ppm) 1.24,1.35(3H,s), 1.37(3H,d,J=Hz),1.65(1H,dd,J=6,12Hz), 2.23(1H,dd,J=9,12Hz), 3.26(1H,m), 3.64(2H,bs),6.51(1H,d,J=7Hz), 6.62(1H,d,J=7Hz), 7.06(1H,t,J=7Hz).

Addition of the chiral solvating agent[(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol] showed the product compriseda 2/1 mixture of R and S enantiomers respectively, as determined byintegration of the highest field methyl signals. (The signal from the Risomer resonates downfield from that of the S isomer).

B. Route No. 2 (i) Preparation of1-(2S-2-Acetoxypropionyl)-1,2-Dihydro-2,2,4-Trimethylquinoline

[R¹ =methyl; R² =H; R³ =R⁴ =methyl; R⁵ =methyl; and R⁶ =-OAc, in thecompound of general formula II].

To L(+) -acetoxylactic acid (72 g, 0.55 moles) in tetrahydrofuran (500ml) was added 1,3-dicyclohexylcarbodiimide (DCC, 56 g, 0.27 moles) intetrahydrofuran (150 ml) at ambient temperature and stirred for 1.5hours. The solid urea by-product was filtered and the filtrate flashedfree of solvent. The 1,2-dihydro-2,2,4-trimethylquinoline (38 g, 0.22moles) was added and the mixture heated at 100° C. for 8 hours. Theproducts were partitioned diethyl ether/water and the organic layerback-washed (5N HCl then sodium bicarbonate) dried (MgSO₄) and freed ofsolvent to give the amide (59 g, gas chromatography showed purity 87%,yield 81%) as an oil.

NMR(CDCl₃): δ (ppm) 1.22 (3H,d,J=7Hz), 1.25,1.64,2.02,2.09(3H,s),5.51(1H,s), 5.64(1H,q,J=7Hz), 7.1-7.3(3H,m), 7.38(1H,bd).

(ii) Preparation of 1-(2-Acetoxypropionyl)-1,2,3,4-Tetrahydro-2,2,4-Trimethylquinoline

[R¹ =methyl; R² =H; R³ =R⁴ =methyl; R⁵ =methyl; and R⁶ =--OAc in thecompound of general formula III].

A mixture of the compound prepared in B(i) (58 g, GC purity 87%, 0.175moles) in acetic acid (250 ml) containing 5% palladium-on-carboncatalyst (3 g) was hydrogenated at atmospheric pressure and ambienttemperature over 8 hours. A total of 3.3 liters of hydrogen was takenup. The catalyst was filtered off and the filtrate stripped of solventand partitioned between toluene/sodium bicarbonate. Solvent flash leftthe reduced amide as an oil (57 g, gas chromatography showed purity 91%,yield 100%). NMR/GC analysis showed the presence of diastereomers in a70/30 ratio.

(major isomer:4R,2S) NMR(CDCl₃) δ (ppm)1.11,1.33(3H,d,J=7Hz),1.15(1H,t,J=12Hz), 1.46,1.63,2.16(3H, s),1.85(1H,dd,J=3,12Hz), 2.68(1H,m), 5.62(1H,q,J=7Hz), 7.1-7.3(3H,m),7.55(1H,m) .

(iii) Preparation of 4-Amino-1,1,3-Trimethylindane

The acetate compound prepared in B(ii) (55 g, GC purity 91% 0 172 moles)was added over 45 minutes to 98% H₂ SO₄ (50 ml) at 25°-60° C.(exotherm). After stirring for a further 30 minutes at 60° C., water (50ml) containing acetic acid (10 ml) was cautiously added dropwise and themixture heated at 100° C. for 3 hours. Petrol (60/80 b.p., 100 ml) wasadded and the mixture basified to pH 9 with 35% aqueous ammonia (150ml). Separation of the organic layer, drying (MgSO₄) and solvent flashgave the desired product (22.6 g, GC purity 92%, yield 69%). NMRanalysis using chiral solvatingagent[(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol] showed a 70/30 mixtureof enantiomers in favour of the (-)-isomer.

EXAMPLE 2 Preparation of4-Methyl-N-(1,1,3-Trimethylindan-4-yl)Thiazole-5-Carboxamide [Enrichedin the 4-Methyl-N-(3R-1,1,3-Trimethylindan,4-yl)Thiazole-5-CarboxamideStereoisomer]

This compound may be prepared by reaching 4-amino-1,1,3-trimethylindaneprepared in Example 1 with 4-methylthiazole-5-carboxylic acid chlorideunder conditions analogous to the conditions described in JapaneseLaid-Open Publication No. 92-54173.

EXAMPLE 3 Pesticidal Activity

The compound prepared in Example 2 has been found to be fungicidal.Additionally, the fungicidal activity of the 3R enantiomer has beenfound to be greater than that of the corresponding 3S enantiomer.

I claim:
 1. A process for the preparation of an indanylamine compound offormula ##STR17## wherein R¹ represents an optionally substituted alkylgroup, and R², R³ and R⁴ independently represent a hydrogen atom or anoptionally substituted alkyl group, the process comprisinghydrogenatinga compound of formula ##STR18## wherein R¹, R², R³ and R⁴ are asdescribed above, and R⁵ and R⁶ independently represent a halogen atom, ahydroxyl, nitro or cyano group, or an optionally substituted alkyl,alkoxy, alkoxycarbonyl, alkylcarboxy or alkylamino group, provided thatR⁵ and R⁶ represent different atoms or groups, to form a firstintermediate compound of formula ##STR19## wherein R¹ to R⁶ are asdescribed above: rearranging the first intermediate compound of formulaIII with a strong acid to form a second intermediate compound of formula##STR20## wherein R¹ to R⁶ are as described above: and hydrolyzing thesecond intermediate compound of formula IV with a weak acid in thepresence of water.
 2. The process according to claim 1, wherein R¹, R³and R⁴ represent a methyl group and R² represents a hydrogen atom. 3.The process according to claim 2 wherein R⁵ represents a C₁₋₆ alkylgroup and R⁶ represents a chlorine atom, or a hydroxyl or C₁₋₆alkylcarboxy group.
 4. A process for the preparation of an intermediatecompound of formula ##STR21## wherein R₁ represents an optionallysubstituted alkyl group, R² R³ and R⁴ independently represent a hydrogenatom or an optionally substituted alkyl group, and R⁵ and R⁶independently represent a halogen atom, a hydroxyl, nitro or cyanogroup, or an optionally substituted alkyl, alkoxy, alkoxycarbonyl,alkylcarboxy or alkylamino group, provided that R⁵ and R⁶ representdifferent atoms or groups, which comprises rearranging an intermediatecompound of formula ##STR22## wherein R¹ to R⁶ are as described above,with a strong acid.
 5. A process for the preparation of a compound offormula ##STR23## wherein A represents a group selected from the groupconsisting of ##STR24## wherein X represents a halogen atom, a methylgroup or a trifluoromethyl group, Y represents a hydrogen atom, ahalogen atom, a lower alkyl group, an amino group, a mercapto group or alower alkylthio group, R¹¹ represents a methyl group or atrifluoromethyl group, R¹² and R¹³ independently represent a hydrogenatom or a methyl group, R¹ represents an optionally substituted alkylgroup, and R², R³ and R⁴ independently represent a hydrogen atom or anoptionally substituted alkyl group, which comprises the steps of(a)hydrogenating a compound of formula ##STR25## wherein R¹, R², R³ and R⁴are as described above and R⁵ and R⁶ independently represent a halogenatom, a hydroxyl, nitro or cyano group, or an optionally substitutedalkyl, alkoxy, alkylcarbonyl, alkylcarboxy or alkylamino group providedthat R⁵ and R⁶ represent different atoms or groups to form a firstintermediate compound of formula ##STR26## wherein R¹ to R⁶ are asdescribed above; (b) rearranging the first intermediate compound offormula III with a strong acid to form a second intermediate compound offormula ##STR27## wherein R¹ to R⁶ are as described above; (c)hydrolyzing the second intermediate compound of formula IV with a weakacid in the presence of water to form an indanylamine compound offormula ##STR28## wherein R¹ to R⁴ are as described above; and (d)reacting the indanylamine compound of formula I with a compound offormula ##STR29## wherein A is as described above and L² represents ahalogen atom, or a hydroxyl, azide, alkoxy, optionally substitutedphenoxy, alkylcarboxy or alkoxycarboxy group.
 6. The process accordingto claim 5, wherein A is ##STR30## in said compound of general formulaVIII.